IGF-1R SPECIFIC ANTIBODIES USEFUL IN THE DETECTION AND DIAGNOSIS OF CELLULAR PROLIFERATIVE DISORDERS
First Claim
1. An antibody or an antigen-binding portion thereof that specifically binds insulin-like growth factor I receptor (IGF-IR), comprising at least one light chain sequence and at least one heavy chain sequence, wherein said light chain comprises at least one complementarity determining region (CDR) selected from the group consisting of the amino acids sequences as set forth in SEQ ID NO. 1, 2, or 3, or at least one CDR comprising an amino acid sequence having at least 80% identity with the sequence set forth in SEQ ID NO. 1, 2, or 3, and wherein said heavy chain comprises at least one complementarity determining region (CDR) selected from the group consisting of the amino acids sequences as set forth in SEQ ID NO. 4, 5 or 6, or at least one CDR comprising an amino acid sequence having at least 80% identity after with the sequence set forth in SEQ ID NO. 4, 5 or 6.
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Abstract
The present invention relates to mammalian antibodies, designated 12B1 and antigen-binding portions thereof that specifically bind to insulin-like growth factor I receptor (IGF-IR), preferably human IGF-IR. Also included are chimeric, bispecific, derivatized, single chain antibodies derived from the antibodies disclosed herein. Nucleic acid molecules encoding the mammalian antibodies as well as methods of use thereof are also disclosed. Also included are pharmaceutical compositions comprising these antibodies and methods of using the antibodies and compositions thereof for treatment and diagnosis of pathological hyperproliferative oncogenic disorders associated with expression of IGf-1R.
190 Citations
73 Claims
- 1. An antibody or an antigen-binding portion thereof that specifically binds insulin-like growth factor I receptor (IGF-IR), comprising at least one light chain sequence and at least one heavy chain sequence, wherein said light chain comprises at least one complementarity determining region (CDR) selected from the group consisting of the amino acids sequences as set forth in SEQ ID NO. 1, 2, or 3, or at least one CDR comprising an amino acid sequence having at least 80% identity with the sequence set forth in SEQ ID NO. 1, 2, or 3, and wherein said heavy chain comprises at least one complementarity determining region (CDR) selected from the group consisting of the amino acids sequences as set forth in SEQ ID NO. 4, 5 or 6, or at least one CDR comprising an amino acid sequence having at least 80% identity after with the sequence set forth in SEQ ID NO. 4, 5 or 6.
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4. A monoclonal antibody that specifically binds insulin-like growth factor I receptor (IGF-IR) or an antigen-binding portion of said antibody, wherein the antibody or antigen-binding portion comprises the amino acid sequences of at least one CDR selected from the group consisting of CDR1, CDR2 and CDR3 regions found in the variable domain of a light chain as set forth in SEQ ID NO:
- 7 and the amino acid sequences of at least one CDR selected from the group consisting of CDR1, CDR2 and CDR3 regions found in the variable domain of a heavy chain as set forth in SEQ ID NO;
8.
- 7 and the amino acid sequences of at least one CDR selected from the group consisting of CDR1, CDR2 and CDR3 regions found in the variable domain of a heavy chain as set forth in SEQ ID NO;
- 5. A hybridoma cell line deposited at the Centre National de Culture De Microorganisme (CNCM, National Center of Microorganism Culture) (Institut Pasteur, Paris, France) under the number I-3538.
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10. A method for selecting a therapy for a patient or a patient population with a tumor associated with or mediated by expression of IGF-1R comprising:
- (a) determining whether the patient'"'"'s tumor is known to over express IGF-1R bearing cells relative to normal and (b) selecting an IGF-1R inhibitory agent as the therapy if the patient'"'"'s tumor is known to over express said IGF-1R.
- View Dependent Claims (11)
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15. A method for determining the prognosis for survival for a patient presenting with a sarcoma selected from the group consisting of osteosarcoma, neuroblastoma, Ewings sarcoma and Rhabdomyo-sarcoma, comprising:
- (a) measuring a level of IGF-1R polypeptide in a cancer cell-containing sample from said patient, and (b) comparing the level of IGF-1R polypeptide in said sample to a reference level of IGF-1R polypeptide from normal tissue, wherein a lower level of IGF-1R polypeptide relative to said reference level correlates with increased survival of said patient.
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16. A method for prognostic evaluation of a patient suspected of exhibiting an oncogenic disorder associated with expression of IGF-1R comprising:
- (a) determining the concentration of IGF-1R present in a biological sample, taken from the patient, suspected of containing oncogenic tissue;
(b) comparing the level determined in step (a) to the concentration range of IGF-1R polypeptide known to be present in normal, non-oncogenic tissue of the same type as present in the biological sample; and
(c) evaluating the prognosis of said patient based on the comparison in step (b), wherein a high level of IGF-1R in step (a) indicates an aggressive form of cancer and therefore a poor prognosis. - View Dependent Claims (17, 18)
- (a) determining the concentration of IGF-1R present in a biological sample, taken from the patient, suspected of containing oncogenic tissue;
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19. A method for determining the prognosis of an individual with an oncogenic disorder or a susceptibility to a pathological hyperproliferative disorder associated with expression of IGF-1R in a subject, comprising:
- a) determining the expression levels of IGF-1R in a biological sample collected from said patient in different states of the individual; and
b) comparing the expression profile of IGF-1R in the different states, wherein a higher level of the expression in a later state compared with an early state indicates a poor prognosis.
- a) determining the expression levels of IGF-1R in a biological sample collected from said patient in different states of the individual; and
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20. A method of detecting a pathological hyperproliferative oncogenic disorder associated with expression of IGF-1R in a subject comprising:
- a) determining the level of expression of IGF-1R in a first tissue sample obtained from said first individual; and
b) comparing said level obtained in step (a) with that of a normal tissue sample obtained from said first individual or a second unaffected individual;
wherein a difference in said expression of IGF-1R is an indication that the first individual may present have said pathological hyperproliferative oncogenic disorder. - View Dependent Claims (21)
- a) determining the level of expression of IGF-1R in a first tissue sample obtained from said first individual; and
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32. An article of manufacture, comprising:
- a container;
a label on the container; and
a composition comprising an active agent contained within the container, wherein the composition is effective for detecting IGF-1R in neoplastic tissue or dysplastic cells and wherein the label on the container indicates that the composition is effective for diagnosing conditions associated with expression of IGF-1R polypeptide in said neoplastic tissue compared to normal tissue.
- a container;
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37. A method for determining whether a cancer is susceptible to treatment with an anti-neoplastic agent comprising the steps of:
- (a) obtaining a sample of the cancer, (b) measuring the level of IGF-1R in the sample, (c) comparing the level with a predetermined value, and (d) determining that, if the measured level is larger than the predetermined value, the cancer is susceptible to treatment with the anti-neoplastic agent.
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50. A diagnostic or monitoring method comprising:
- a) obtaining a sample of tissue from an individual in need of diagnosis or monitoring for cancer;
b) detecting levels of IGF-1R protein in said sample, c) scoring said sample for IGF-1R protein levels; and
d) comparing said scoring to that obtained from a control tissue sample to determine the prognosis associated with said cancer. - View Dependent Claims (51, 52, 53, 54, 55)
- a) obtaining a sample of tissue from an individual in need of diagnosis or monitoring for cancer;
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56. A method for determining a chemotherapeutic regimen comprising an IGF-1R targeted agent, for treating a tumor in a patient comprising:
- (a) obtaining a tissue sample of the tumor;
(b) detecting levels of IGF-1R levels in said sample, (c) scoring said sample for expression of IGF-1R levels, (d) repeating steps (b)-(c) in a matching non-malignant tissue sample to obtain a threshold level (e) determining a chemotherapeutic regimen by comparing the differential IGF-1R expression level of step (c) and the threshold level of step (d), wherein an increase in differential IGF-1R expression level in step (c) relative to step (d) dictate placing said patient in the chemotherapeutic regimen. - View Dependent Claims (57, 58)
- (a) obtaining a tissue sample of the tumor;
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59. A method for predicting disease-free survival and overall survival in a patient with an oncogenic disorder associated with IGF-1R expression comprising:
- a) obtaining a sample of diseased or cancerous tissue from an individual presenting with said oncogenic disorder, b) detecting levels of IGF-1R expressing cells in said cancer cells or cancer tissue of said sample;
c) scoring said samples for expression of IGF-1R levels; and
d) comparing said scoring to that obtained from a control sample to determine likelihood of disease-free survival and overall survival associated with IGF-1R. - View Dependent Claims (60, 61)
- a) obtaining a sample of diseased or cancerous tissue from an individual presenting with said oncogenic disorder, b) detecting levels of IGF-1R expressing cells in said cancer cells or cancer tissue of said sample;
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62. A method for treating an IGF-1R mediated cancer comprising:
- a) obtaining a sample of diseased tissue from a patient in need of treatment of said cancer;
b) determining the level of expression of IGF-1R levels in said tissue sample;
c) scoring said samples for expression of IGF-1R levels;
d) correlating said score to identify patients likely to benefit from treatment with an IGF-1R antagonist, wherein said step of correlating comprises comparing said scoring to that obtained from a control sample, e) treating said patient with a therapeutic regime known to improve the prognosis for said cancer;
f) repeating steps “
a” and
“
b”
, and g) adjusting the therapeutic regime known to improve the prognosis for said cancer;
h) repeating steps a-f as frequently as deemed appropriate. - View Dependent Claims (63, 64)
- a) obtaining a sample of diseased tissue from a patient in need of treatment of said cancer;
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65. A method for determining the effect of a therapeutic regimen for alleviating an IGF-1R mediated disorder, wherein said regimen comprises the use of an IGF-1R antagonist, the method comprising the steps of:
- a) obtaining a cell or tissue sample from an individual undergoing said therapeutic regimen b) measuring the levels of IGF-1R in said cell or tissue sample;
c) scoring said sample for IGF-1R protein levels, and d) comparing said levels to that of a control sample to predict the responsiveness of said IGF-1R mediated disorder to said therapeutic regimen. - View Dependent Claims (66, 67)
- a) obtaining a cell or tissue sample from an individual undergoing said therapeutic regimen b) measuring the levels of IGF-1R in said cell or tissue sample;
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68. A method for stratifying a patient presenting with an oncogenic disorder mediated by IGF-1R for a clinical trial comprising:
- a) obtaining a tissue sample from said patient, b) detecting levels of IGF-1R protein in said sample, c) scoring said sample for IGF-1R protein levels; and
d) stratifying said patient for said clinical trial based on the results of the scoring step. - View Dependent Claims (69, 70)
- a) obtaining a tissue sample from said patient, b) detecting levels of IGF-1R protein in said sample, c) scoring said sample for IGF-1R protein levels; and
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71. A method of classifying or staging a breast tumor characterized by expression of IGF-1R comprising the steps of:
- i) providing a breast tumor sample, ii) detecting expression IGF-1R in the sample, iii) scoring the sample for IGF-1R expression level, and iv) classifying the tumor as belonging to a tumor subclass based on the results of the scoring step.
- View Dependent Claims (72, 73)
Specification